Malignancies, such as infiltrative brain tumors and breast cancer (e.g., triple-negative breast cancer), often result in poor prognosis due to incomplete detection, resistance to treatment, and failure to eliminate of invasive tumor cells that migrate distant from the tumor. For example, malignant gliomas account for 70% of all brain tumors in adults (Wen & Kesari 2008) and approximately 190,000 patients are diagnosed every year (Parkin et al. 2002). There is currently no cure for this condition, and the majority of patients diagnosed with malignant gliomas die within 1 year (Parkin et al. 2002). Malignant gliomas are conventionally treated by surgery, radiotherapy, and chemotherapy (Castro et al. 2003). This treatment regimen, though aggressive, is almost always futile because tumor resurgence is common (King et al. 2005).
Several reasons may explain why these tumors are so resistant to treatment. First, once malignant transformation occurs, the glioma cells extensively infiltrate into normal brain parenchyma through the dense network of neuronal and glial cell processes and/or disseminate via cerebrospinal fluid pathways to generate distant tumor foci called microsatellites (Claes et al. 2007). Current treatment regimens fail to eliminate microsatellites. Limitations of current imaging technology makes the possibility of identifying and removing all tumor microsatellites by surgical excision unlikely because diffuse infiltration of glioma cells usually spreads beyond evident tumor boundaries (Yu & Ehtesham 2008; Wen & Kesari 2008). Invasive glioma cells also escape localized radiation therapy (Stupp et al. 2005), and chemotherapy has limited impact on the outcome of malignant gliomas because of difficulties delivering drugs across the blood-brain barrier and the lack of specificity of chemotherapeutic drugs for tumor cells (Deeken & Loscher 2007; Penas-Prado & Glibert 2007).
Another reason malignant gliomas may be so resistant to treatment is due to the heterogeneous cell composition of these tumors, which results in the emergence of drug-resistant cell populations (Cowen et al. 2002). Further, current treatment regimens fail to eliminate CD133+ malignant glioma tumor stem cells that may survive or escape treatment and cause recurrence of a tumor (Furnari et al. 2007).
Despite the development of magnetic resonance imaging (MRI) contrast enhancing agents such as superparamagnetic iron-oxide nanoparticles (SPIONs) (Shubayev et al. 2009; Arbab et al. 2005), improved formulations of standard tumor-toxic small molecule compounds such as Temozolomide (194.151 g/mol) (Zhang et al. 2010), and newer tumor-ligand specific toxic drugs such as targeted toxins directed against the IL-13 receptor (Kunwar 2003), the IL-4 receptor (Weber et al. 2003), the TGF-α receptor (Sampson et al. 2003), and the transferrin receptor (Laske et al. 1997); complete elimination of invasive cells has not been practicable given the inability to accurately detect the full extent of tumor cells or selectively deliver these agents to isolated invasive cells at effective concentrations (Zhang et al. 2010; Peer et al. 2007; Gullotti & Yeo 2009).
Many of the factors that contribute to the difficulty of treating malignant glioma also apply to other malignancies and cancers. Therefore, new carriers and therapeutic regimens that are capable of distinguishing between normal and malignant cells, eliminating heterogeneous populations of cancer cells and eliminating CD133+ cancer stem cells without harming healthy cells, and targeting tumor cells and diffuse glioma microsatellites are needed.